"The U.S. Food and Drug Administration today approved Lymphoseek (technetium Tc 99m tilmanocept) Injection, a radioactive diagnostic imaging agent that helps doctors locate lymph nodes in patients with breast cancer or melanoma who are undergoing "...
Mechanism of Action
Tositumomab binds specifically to an epitope within the extracellular domain of the CD20 molecule. The CD20 molecule is expressed on normal B lymphocytes (pre-B lymphocytes to mature B lymphocytes) and on B-cell non-Hodgkin's lymphomas. The CD20 molecule is not shed from the cell surface and is not internalized following antibody binding. The BEXXAR therapeutic regimen induces cell death by emitting ionizing radiation to CD20-expressing lymphocytes or neighboring cells. In addition to cell death mediated by the radioisotope, other possible mechanisms of action include antibody-dependent cellular cytotoxicity, complement- dependent cytotoxicity, and CD20-mediated apoptosis.
In two clinical studies (one in chemotherapy-naive patients and one in heavily pretreated patients), the administration of the BEXXAR therapeutic regimen resulted in sustained depletion of circulating CD20-positive cells. The assessment of circulating lymphocytes in these patients did not distinguish normal from malignant cells; consequently, recovery of normal B cell numbers was not directly assessed. At 7 weeks following treatment, the median number of circulating CD20-positive cells was zero (range: 0 to 490 cells/mm³) with recovery beginning at approximately 12 weeks. At 6 months following treatment, 8 (14%) of 58 chemotherapy-na´ve patients and 6 (32%) of 19 heavily pretreated patients had CD20-positive cell counts below normal limits. There was no consistent effect of the BEXXAR therapeutic regimen on posttreatment serum IgG, IgA, or IgM levels.
A pharmacokinetic study of I-131 tositumomab determined that a 475-mg predose of unlabeled antibody decreased splenic targeting and increased the terminal half-life of the radiolabeled antibody. The median blood clearance following administration of 485 mg of tositumomab in 110 patients with non-Hodgkin's lymphomas was 68.2 mg/hr (range: 30.2 to 260.8 mg/hr). Patients with high tumor burden, splenomegaly, or bone marrow involvement were noted to have a larger volume of distribution, faster clearance, and shorter terminal half-life. The total body clearance, as measured by total body gamma camera counts, was dependent on the same factors noted for blood clearance. Patient-specific dosing, based on total body clearance, provided a consistent radiation dose despite variable pharmacokinetics, by allowing each patient's administered activity to be adjusted for individual patient variables. The median total body effective half-life, as measured by total body gamma camera counts, in 980 patients with non-Hodgkin's lymphoma was 67 hours (range: 28 to 115 hours).
Elimination of Iodine-131 occurs by decay (Table 5) and excretion in the urine. Five days following the dose, the whole body clearance was 67% of the injected dose. Ninety-eight percent (98%) of the clearance was accounted for in the urine.
The clinical benefit of the BEXXAR therapeutic regimen was established in a single-arm clinical trial conducted in 40 patients with low-grade, transformed low-grade, or follicular largecell lymphoma. Patients had a Karnofsky performance status of at least 60%, a granulocyte count of 1500 cells/mm³, a platelet count greater than or equal to 100,000/mm³, less than or equal to 25% of the intra-trabecular marrow space involved by lymphoma, and no evidence of progressive disease arising in a field irradiated with > 3500 cGy within one year of completion of irradiation.
This study enrolled 40 patients with low-grade or transformed low-grade or follicular large-cell lymphoma whose disease had not responded to, or had progressed following, at least 4 doses of rituximab therapy. The median age was 57 years (range: 35 to 78 years); the median time from diagnosis to protocol entry was 50 months (range: 12 to 170 months); and the median number of prior chemotherapy regimens was 4 (range: 1 to 11). Overall, 35 of the 40 patients were rituximab-refractory (defined as no response or a response of less than 6 months' duration following rituximab therapy).
The main outcome measure was overall response rate as determined by an independent panel that reviewed patient records and radiologic studies (Table 6).
Table 6: Efficacy Outcomes for the BEXXAR Therapeutic
|Response||n = 40|
|95% CIa||(51%, 81%)|
|Response Duration (months)|
|95% CIa||(10, NRb)|
|Range||1+ to 38+|
|95% CIa||(19%, 49%)|
|Complete Responsec Response Duration (months)|
|95% CIa||(15, NR)|
|Range||4 to 38+|
|a CI = confidence interval
b NR = not reached, median duration of follow-up = 26 months
c Complete response rate = pathologic and clinical complete responses
The results of this study were supported by demonstration of durable objective responses in 4 single-arm studies enrolling 190 patients evaluable for efficacy with rituximab-naive, follicular non-Hodgkin's lymphoma with or without transformation, who had relapsed following or were refractory to chemotherapy. In these studies, the overall response rates ranged from 47% to 64% and the median durations of response ranged from 12 to 18 months.
Last reviewed on RxList: 9/27/2012
This monograph has been modified to include the generic and brand name in many instances.
Additional Bexxar Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Get the latest treatment options.